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. 2026 Jan;22(1):668-675.
doi: 10.1007/s12015-025-10984-8. Epub 2025 Sep 25.

Vascular Organoids Derived from Capillary malformation-induced Pluripotent Stem Cells Exhibit Disease-Relevant Phenotypes

Vi Nguyen  1 , Anna Harper  1 , Mackenzie Azuero  1 , Isabella Castellanos  1 , Siwuxie He  1 , Marcelo L Hochman  2   3 , Camilla F Wenceslau  1   4 , Dong-Bao Chen  5 , Anil G Jegga  6   7 , Yunguan Wang  6   8 , Daping Fan  1   4 , J Stuart Nelson  9 , Wenbin Tan  10   11
Affiliations

Vascular Organoids Derived from Capillary malformation-induced Pluripotent Stem Cells Exhibit Disease-Relevant Phenotypes

Vi Nguyen et al. Stem Cell Rev Rep. 2026 Jan.

Abstract

Capillary malformation (CM) is a congenital vascular anomaly that affects the skin, mucosa, eye, and brain. A major obstacle to mechanistic and drug screening studies for CM has been the lack of preclinical models. In this study, we established vascular organoids (VOs) generated through the self-assembly of vascular lineages of endothelial cells and smooth muscle cells differentiated from CM-induced pluripotent stem cells (iPSC). Within these VOs induced endothelial cells and smooth muscle cells organized into juxtapositions to form vascular branches. CM patient iPSC-derived VOs showed a higher density of endothelial and smooth muscle cell populations and greater vascular branch lengths as compared with VOs derived from iPSCs generated from healthy skin biopsies. Overall, this study represents the first disease-relevant VO model of CM, providing a valuable platform for future mechanistic studies and drug screening.

Keywords: Capillary Malformation; Endothelial Cells; Human Induced Pluripotent Stem Cells; Smooth Muscle Cells; Vascular Organoid.

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Conflict of interest statement

Declarations. Competing Interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
VOs induction from normal and CM iPSCs. A: Schematic of VO differentiation protocol. B and C: Whole mount IF staining was performed to show 3D structures of control (B) and CM VO (C) using an anti-CDH5 (a.k.a. CD144) (green), anti-UEA1 (light blue), and anti-aSMA (red) antibody. Images were acquired using Zeiss light sheet fluorescence microscopy and presented in maximum intensity projection mode (Zeiss Zen software). DAPI staining was used to reveal nuclei (dark blue). Overlay images of CDH5/aSMA, UEA1/DAPI, UEA1/CDH5/DAPI, and UEA1/CDH5/aSMA/DAPI were shown in each panel
Fig. 2
Fig. 2
Structural characterizations of CM VOs. A and B: Cross sections of control (A) or CM (B) VO with IF staining of CDH5 (green), UEA1 (light blue), aSMA (red), or overlay of CDH5/aSMA/DAPI, UEA1/aSMA/DAPI, and CDH5/UEA1/aSMA/DAPI. C-F: higher magnifications of red (C, E) or yellow (D, F) boxed areas from (A) and (B), respectively, showing juxtapositions of iECs and iSMCs (yellow arrowheads) in vascular branches. G: UEA1, CDH5 or aSMA positive cell density (per mm2) in control and CM VOs. H: Distribution of vascular branch length in arbitrary unit. I: Arbitrary vascular branch length in control and CM VOs. #, p < 0.005 as compared to the control group, paired t-test; &, p = 1.56 × 10−33 as compared to the control group, Mann-Whitney U test. N = 3 VOs per group and 4–8 cross sections for (G) and (I) per VO
See this image and copyright information in PMC

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